Approximately twenty percent of deaths from all causes in the United States are cancer-related. Although chemotherapy is a principal means of cancer treatment, the rate at which effective new drugs have become available for use in cancer chemotherapy has not increased (Horowitz et al., Journal of Clinical Oncology, Vol. 6, No. 2, pp. 308-314 (1988)). Despite many years of promising new therapies, cancer remains a major cause of morbidity and mortality. (Bailar et al., N. Engl. J. Med. 336:1569-1574, 1997) Accordingly, there is a substantial need for new drugs which are effective in inhibiting the growth of tumors.
Cardiac glycosides are potent and highly selective inhibitors of the active transport of Na+ and K+ across cell membranes and act by binding to the alpha subunit of the Na+ K+-ATPase. The affinity of the alpha subunit for cardiac glycosides varies among species and among the three known mammalian alpha subunit isoforms, each of which is encoded by a separate gene. (Goodman and Gilman, xe2x80x9cThe Pharmacological Basis of Therapeutics, 9th edition, Hardman and Limbird eds, p. 810 (1996)). These compounds share a steroid nucleus containing an unsaturated lactone ring at the C17 position and one or more glycosidic residues at C3, and occur naturally in many plants and several toad species, usually acting as venoms or toxins that serve as protection against predators. (Id).
Cardiac glycosides have been used extensively as therapeutics in the treatment of heart failure. (Goodman and Gilman, xe2x80x9cThe Pharmacological Basis of Therapeutics, 9th edition, Hardman and Limbird eds, p. 810 (1996)). Digitoxin has been the most widely used cardiac glycoside, with a therapeutic plasma concentration of greater than 10 ng/ml (approximately 13 nM). However, digitoxin is toxic at concentrations of above 35 ng/ml (approximately 46 nM) (Id. at 1736). Thus, the therapeutic window for digitoxin in the treatment of heart failure is quite narrow.
Cardiac glycosides have also been shown to inhibit cell proliferation in a wide variety of cell lines in vitro. (See for example Kaneda et al., Planta Med. 58:429-431 (1992), Gil et al., J. Natural Products 58:848-856 (1995), Kitinaka et al., Chem. Pharm. Bull. 44(3):615-617 (1996), Baek et al., Planta Med. 60(1):26-29 (1994), Zhang et al., Chinese Medical Journal 109(6):478-481 (1996), Shiratori, GANN 58:521-528 (1967), Doskotch et al., J. Pharmaceutical Sciences 61(4):570-573 (1972), Kupchan et al., J. Med. Chem 17:803 (1964), Kupchan et al., Science 146:1685 (1964), Hyun et al., Planta Med. 61:294-295 (1995), Al-Said et al., Phytochemistry 27(10):3245-3250 (1988)). This in vitro activity was routinely shown to be non-selective, as the proliferation of almost all tumor cell lines were inhibited, and occurred at similar (generally toxic) doses across the different cell lines. Studies have also suggested that cardiac glycosides can be used to inhibit the export of leaderless proteins from cells (U.S. Pat. No. 5,891,855), as well as inhibiting inflammatory cytokine secretion (U.S. Pat. No. 5,545,623), but only at toxic doses.
Based on these in vitro findings, numerous cardiac glycosides have been screened for their ability to inhibit in vivo tumor growth. (See, for example, LeWinn, The Lancet Jun. 2, 1979, p. 1196-1197; Stenkvist et al., The Lancet Mar. 10, 1979 p. 563; Stenkvist et al., The Lancet Feb. 25, 1982, p. 484.) However, the results of these in vivo studies have uniformly proven disappointing, as any therapeutic activity was found only at toxic doses. (Repke et al., Anti-Cancer Drug Design 10:177-187 (1995)). Based on all of these studies, the use of cardiac glycosides as effective anti-neoplastic agents would be entirely unexpected.
The present invention is based on the entirely unexpected finding that digitoxin can act as an effective anti-neoplastic agent. In one aspect, the present invention provides novel methods for treating tumors that involve administering an effective amount of digitoxin, or a pharmaceutical salt thereof, to a patient in need of such treatment, wherein the tumor is selected from the group consisting of mesotheliomas, sarcomas, carcinomas, stromal cell, and germ cell tumors.
In further aspects, the present invention provides pharmaceutical compositions comprising an effective amount for treating tumors of digitoxin, or a pharmaceutical salt thereof, in a suitable carrier, and an article of manufacture comprising packaging material and the above pharmaceutical composition.
All references cited herein are incorporated by reference in their entirety.
As used herein, the term xe2x80x9ceffective amountxe2x80x9d means a dosage sufficient to produce adesired result. The desired result can be subjective or objective improvement in the recipient of the dosage, a decrease in tumor size, time to progression of disease, and/or survival.
As used herein the term xe2x80x9cmesotheliomaxe2x80x9d is used to refer to a neoplasm derived from the cells lining the pleura, pericardium, or peritoneum, including but not limited to lung mesotheliomas.
As used herein the term xe2x80x9csarcomaxe2x80x9d refers to tumors of mesenchymal origin, including but not limited to leiomyosarcomas, malignant fibrous histiocytoma, Ewing sarcoma, fibrosarcomas, chondrosarcomas, osteosarcomas, liposarcomas, rhabdomyo-sarcomas, hemangiocytomas, and myxosarcomas.
As used herein the term xe2x80x9ccarcinomaxe2x80x9d is used to refer to a neoplasm derived from epithelial cells.
As used herein the term xe2x80x9covarian carcinomaxe2x80x9d refers to neoplasms derived from ovarian cells of epithelial origin, including but not limited to ovarian papillary serous cystadenoma, ovarian endometroid carcinoma, mucinous, clear cell and Brenner epithelial tumors;
As used herein the term xe2x80x9clung carcinomaxe2x80x9d refers to neoplasms derived from lung cells including but not limited to squamous cell carcinomas, adenocarcinomas, oat cell carcinomas, carcinoid tumors, giant cell tumors, mucoepidermoid tumors, and adenoidcystic carcinomas.
As used herein the term xe2x80x9ckidney carcinomaxe2x80x9d refers to neoplasms derived from kidney cells including but not limited to renal cell carcinomas, Wilm""s tumor, and hamartoma.
As used herein the term xe2x80x9cgerm cell tumorsxe2x80x9d refers to neoplasms including, but not limited to, dysgerminomas, and yolk sac tumors.
As used herein the term xe2x80x9cstromal cell tumorsxe2x80x9d refers to neoplasms including, but not limited to granulosa cell, thecoma, and Sertoli-Leydig tumors.
In one aspect, the present invention provides new methods treating tumors that involve administering an effective amount of digitoxin, or a pharmaceutical salt thereof, to a patient in need of such treatment, wherein the tumor is selected from the group consisting of mesotheliomas, sarcomas, carcinomas, stromal cell, and germ cell tumors.
Digitoxin can be prepared by any of the methods known in the literature. Non-limiting examples of these methods include those disclosed in U.S. Pat. Nos. 3,514,441; 3,531,462; 3,843,628; 3,857,832; 3,939,156; 3,949,074; and 4,001,402, all references incorporated by reference herein in their entirety. Alternatively, digitoxin is commercially available (for example, Sigma Chemical Co., St. Louis, Mo.).
As disclosed herein, digitoxin and pharmaceutical compositions including digitoxin are useful in treating mesotheliomas, sarcomas, carcinomas, stromal cell and germ cell tumors. Examples of specific tumor types that the compounds may be used to treat include, but are not limited to solid tumors including ovarian papillary serous cystadenoma and ovarian endometroid carcinoma, lung mesothelioma, malignant fibrous histiocytoma, leiomyosarcoma, Ewing sarcoma, hemangiocytomas. Other ovarian tumors, such as mucinous, clear cell and Brenner epithelial tumors; germ cell tumors including dysgerminomas and yolk sac tumors; and stromal cell tumors including granulosa cell, thecoma, and Sertoli-Leydig tumors, are also treatable. Other sarcomas treatable with the compounds of the invention include fibrosarcomas, chondrosarcomas, osteosarcomas, liposarcomas, rhabdomyosarcomas, and myxosarcomas.
Preferred examples of carcinomas that may be treated with digitoxin include ovarian, kidney, and lung carcinomas.
In another preferred embodiment, digitoxin is used to treat ovarian papillary serous cystadenomas, ovarian endometroid carcinomas, mesotheliomas, malignant fibrous histiocytomas (a sarcoma), leiomyosarcomas, hemangiocytomas, liposarcomas, and Ewing sarcomas.
The digitoxin can be administered individually or in combination with other anti-tumor agents, usually in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, the present invention also includes pharmaceutical compositions comprising as active ingredient digitoxin associated with a pharmaceutically acceptable carrier, and the invention further comprises the method of treating susceptible neoplasms using the compositions containing digitoxin.
The digitoxin can be administered as the sole active pharmaceutical agent, or they can be used in combination with one or more other anti-tumor agents. When administered as a combination, the digitoxin and other anti-tumor agents can be formulated as separate compositions that are given at the same time or different times, or they can be given as a single composition.
The digitoxin may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The digitoxin may be applied in a variety of solutions and may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
For administration, digitoxin is ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
Pharmaceutical compositions containing digitoxin are administered to an individual having a tumor. In therapeutic applications, compositions are administered to a human patient in an amount sufficient to cause regression of the tumor, or at least partially arrest tumorigenesis and metastasis. Amounts effective for this use depend on factors including, but not limited to, the nature of the compound (specific activity, etc.), the manner of administration, the stage and severity of the cancer, the weight and general state of health of the patient, and the judgment of the prescribing physician. The digitoxin is effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 1 xcexcg/kg to about 0.8 mg/kg of body weight. In the treatment of adult humans, the range of about 1 xcexcg/kg to about 0.1 mg/kg of body weight, in single or divided doses, is preferred, while 5 xcexcg/kg to about 30 xcexcg/kg is most preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the chosen route of administration, the age, weight, and response of the individual patient, disorders affecting the heart, and other specific organ dysfunction, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
The digitoxin may be administered by any suitable route, including orally, parentally, by inhalation or rectally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles, including liposomes. The term parenteral as used herein includes, subcutaneous, intravenous, intraarterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques, intracavity, or intraperitoneally. In a preferred embodiment, the compounds of the invention are administered orally or parentally.
The instant invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof. The present disclosure and enumerated examples are therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and all equivalency are intended to be embraced therein. One of ordinary skill in the art would be able to recognize equivalent embodiments of the instant invention, and be able to practice such embodiments using the teaching of the instant disclosure and only routine experimentation.